Society and ethics - the genetics of disease

Established guidance for the protection of human subjects in research has provided the framework for research and clinical practice in genetics. Three key principles to emerge are the requirements for consent, privacy and confidentiality. However, recent research on genetic susceptibility to common diseases indicates that it may be more difficult to decide if and when genetic testing will be appropriate. Risks of disease may be low and interventions may not be available. Today, debate is primarily focussed on ethical issues raised by the use and storage of genetic information. One of the earliest experiences of genetic testing for some people is likely to be in the area of pharmacogenetics. Debate about ethical issues has been focused on the implications of patient stratification, particularly with regard to the availability of medicines for small groups and the significance of racial variation in response to medicines. The possible use of personal genetic information by insurance companies and employers has also been an issue that legislators have taken seriously.     

Tailored Medicine: Whom Will it Fit? The Ethics of Patient and Disease Stratification

A key selling point of pharmacogenetics is the genetic stratification of either patients or diseases in order to target the prescribing of medicine. The hope is that genetically 'tailored' medicines will replace the current 'one-size-fits-all' paradigm of drug development and usage. This paper is concerned with the relationship between difference and justice in the use of pharmacogenetics. This new technology, which facilitates the identification and use of difference, has, we shall argue, the potential to lead to injustice either by the inappropriate use of difference or through the inappropriate failure to use difference. We build on empirical data from a detailed study of the range of options for the development of pharmacogenetics to present a consideration of the ethical issues that surround patient and disease stratification. In it we explore the ways in which the use of pharmacogenetics may lead to the creation of new, genetically stratified, forms of difference and new forms of injustice based on these divisions. We also examine the ways in which existing forms of difference and social stratification may interact with the use of pharmacogenetics. In conclusion, we suggest how an understanding of these ethical issues could usefully inform future policy discussions.     

Current status and future potential of somatic mutation testing from circulating free DNA in patients with solid tumours

Genetic alterations can determine the natural history of cancer and its treatment response. With further advances in DNA sequencing technology, multiple novel genetic alterations will be discovered which could be exploited as prognostic, predictive and pharmacodynamic biomarkers in the development and use of cancer therapeutics. As such, the importance in clinical practice of efficient and robust somatic mutation testing in solid tumours cannot be overemphasized in the current era of personalized medicine. However, significant challenges remain regarding the testing of genetic biomarkers in clinical practice. Reliance on archived formalin fixed, paraffin embedded tumour, obtained from diagnostic biopsies, for testing somatic genetic alterations could restrict the scientific community in asking relevant questions about a patient’s cancer biology. Problems inherent with using formalin fixed, archival tissue are well recognized and difficult to resolve. It could be argued that to achieve rapid and efficient incorporation of genetic biomarkers into clinical practice, somatic mutation testing in cancer patients should be simpler, less invasive using a readily available clinical sample, whilst maintaining robustness and reproducibility. In this regard, use of circulating free DNA (cfDNA) from plasma or serum as an alternative and/or additional source of DNA to test cancer specific genetic alterations is an attractive proposition. In light of encouraging results from recent studies, this mini review will discuss the current role and future potential of somatic mutation testing from circulating or cell free DNA derived from the blood of patients with solid tumours.     

Pharmacogenetics of cardiovascular drugs.

Pharmacogenetics is a field aimed at understanding the genetic contribution to inter-patient variability in drug efficacy and toxicity. Treatment of cardiovascular disease is, in most cases, guided by evidence from well-controlled clinical trials. Given the solid scientific basis for the treatment of most cardiovascular diseases, it is common for patients with a given disease to be treated in essentially the same manner. Thus, the clinical trials have been very informative about treating large groups of patients with a given disease, but are slightly less informative about the treatment of individual patients. Pharmacogenetics and pharmacogenomics have the potential of taking the information derived from large clinical trials and further refining it to select the drugs with the greatest likelihood for benefit, and least likelihood for harm, in individual patients, based on their genetic make-up. In this paper, the current literature on cardiovascular pharmacogenetics is emphasised, and how the use of pharmacogenetic/pharmacogenomic information may be particularly useful in the future in the treatment of cardiovascular diseases is also highlighted.     

PHARMACOGENETICS,RACE AND GLOBAL INJUSTICE1

This paper discusses the link between pharmacogenetics and race, and the global justice issues that the introduction of pharmacogenetics in pharmaceutical research and clinical practice will raise. First, it briefly outlines the likely impact of pharmacogenetics on pharmaceutical research and clinical practice within the next five to ten years and then explores the link between pharmacogenetic traits and ‘race’. It is shown that any link between apparent race and pharmacogenetics is problematic and that race cannot be used as a proxy for pharmacogenetic knowledge. The final section considers the implications of the development of pharmacogenetics for health care systems in low‐ and middle‐income countries.     

Attitudes of deaf adults toward genetic testing for hereditary deafness.

Recent advances within molecular genetics to identify the genes for deafness mean that it is now possible for genetic-counseling services to offer genetic testing for deafness to certain families. The purpose of this study is to document the attitudes of deaf adults toward genetic testing for deafness. A structured, self-completion questionnaire was given to delegates at an international conference on the "Deaf Nation," held at the University of Central Lancashire in 1997. The conference was aimed at well-educated people, with an emphasis on Deaf culture issues. Eighty-seven deaf delegates from the United Kingdom returned completed questionnaires. The questionnaire had been designed to quantitatively assess attitudes toward genetics, interest in prenatal diagnosis (PND) for deafness, and preference for having deaf or hearing children. The results from this study provide evidence of a predominantly negative attitude toward genetics and its impact on deaf people, in a population for whom genetic-counseling services are relevant. Fifty-five percent of the sample thought that genetic testing would do more harm than good, 46% thought that its potential use devalued deaf people, and 49% were concerned about new discoveries in genetics. When asked about testing in pregnancy, 16% of participants said that they would consider having PND, and, of these, 29% said that they would prefer to have deaf children. Geneticists need to appreciate that some deaf persons may prefer to have deaf children and may consider the use of genetic technology to achieve this. Any genetic-counseling service set up for families with deafness can only be effective and appropriate if clinicians and counselors take into consideration the beliefs and values of the deaf community at large.     

Differences between African Americans and Whites in their attitudes toward genetic testing for Alzheimer's disease

The possibility of predictive genetic testing for Alzheimer's disease (AD) has prompted examination of public attitudes toward this controversial new health-care option. This is the first study to examine differences between Whites and African Americans with regard to: (1) interest in pursuing genetic testing for AD, (2) reasons for pursuing testing, (3) anticipated consequences of testing, and (4) beliefs about testing. We surveyed a convenience sample of 452 adults (61% white; 39% African American; 78% female; mean age = 47 years; 33% with family history of AD). Both racial groups indicated general interest in predictive genetic testing for AD, viewed it as having many potential benefits, and believed it should be offered with few restrictions. However, in comparison to whites, African Americans showed less interest in testing (p < 0.01), endorsed fewer reasons for pursuing it (p < 0.01), and anticipated fewer negative consequences from a positive test result (p < 0.001). These preliminary findings show important distinctions between whites and African Americans in their attitudes toward genetic testing for AD. These differences may have implications for how different racial and ethnic groups will respond to genetic testing programs and how such services should be designed. Future research in real-life testing situations with more representative samples will be necessary to confirm these racial and cultural differences in perceptions of genetic testing.     

Pharmacogenetics and pharmacogenomics in oncology therapeutic antibody development

Pharmacogenetics and pharmacogenomics are keys to the success of personalized medicine, prescribing drugs based on a patient's individual genetic and biological profile. In this review, we will focus on the application of pharmacogenetics and pharmacogenomics in developing monoclonal antibody (MAb) therapeutics in oncology. The significance of pharmacogenomics in MAb therapeutics is highlighted by the association between polymorphisms in Fc receptors and clinical response to anti-CD20 MAb rituximab (Rituxan) or anti-ganglioside GD2 MAb 3F8, as well as the potential link between polymorphisms in HER2 and cardiac toxicity in patients treated with the anti-HER2 MAb trastuzumab (Herceptin). The dependence on gene copy number or expression levels of HER2 and epidermal growth factor receptor (EGFR) for therapeutic efficacy of trastuzumab and cetuximab (Erbitux), respectively, supports the importance of selecting suitable patient populations based on their pharmacogenetic profile. In addition, a better understanding of target mutation status and biological consequences will benefit MAAb development and may guide clinical development and use of these innovative therapeutics. The application of pharmacogenetics and pharmacogenomics in developing MAb therapeutics will be largely dependent on the discovery of novel surrogate biomarkers and identification of disease- and therapeutics-relevant polymorphisms. Challenges and opportunities in biomarker discovery and validation, and in implementing clinical pharmacogenetics and pharmacogenomics in oncology MAb development and clinical practice will also be discussed.     

Toward a better understanding of ADHD: LPHN3 gene variants and the susceptibility to develop ADHD

During the past 15 years, an impressive amount of genetic information has become available in the research field of psychiatry, particularly as it relates to attention-deficit/hyperactivity disorder (ADHD). However, the classical clinical approach to ADHD has minimally affected and not significantly been improved by this genetic revolution. It is difficult to predict how long it will take for genetic findings to alter the way clinicians treat patients with ADHD. New medications or treatment protocols may take years to become routine clinical practice. However, when taken together, recent successes in genomics, pharmacogenomics, and genetic epidemiology have the potential (1) to prevent comorbid consequences of ADHD, (2) to individualize therapies for patients with ADHD, and (3) to define new epidemiological policies to aid with the impact of ADHD on society. Here, we present an overview of how genetic research may affect and improve the quality of life of patients with ADHD: as an example, we use the discovery of LPHN3, a new gene in which variants have recently been shown to be associated with ADHD.     

Clinical application of pharmacogenetics

Pharmacogenetics encompasses the involvement of genes in an individual's response to drugs. As such, the field covers a vast area including basic drug discovery research, the genetic basis of pharmacokinetics and pharmacodynamics, new drug development, patient genetic testing and clinical patient management. Ultimately, the goal of pharmacogenetics is to predict a patient's genetic response to a specific drug as a means of delivering the best possible medical treatment. By predicting the drug response of an individual, it will be possible to increase the success of therapies and reduce the incidence of adverse side effects.     

Implications of the human genome initiative for the primary care physician

... Despite the need for physicians to be knowledgeable about and open to advances in genetic technology, little is known about the level of preparedness of primary care physicians to offer new genetic tests. Evidence suggests that several barriers exist to physicians adopting genetic tests. These include lack of knowledge, inability to interpret probabilistic information, low tolerance for uncertainty, negative attitudes about their responsibility for genetic counseling and testing, lack of confidence in their clinical skills, and unfamiliarity with ethical issues raised by testing. This paper will explore some of these barriers in further depth, discuss the ethical impact of physician unpreparedness on both patient care and the diffusion of genetic tests, and describe a study that is currently underway to investigate some of these issues.     

Integrating pharmacogenetics into society: in search of a model

There has been considerable scientific, corporate and policy interest in the more effective use of genetics in both drug development and delivery. Pharmacogenetics - the study of the relationship between an individual's genetic makeup and response to medicinal drugs - has attracted global interest, but will it live up to its promise? Looking beyond the hype that has accompanied much of the commentary in the area, the future of pharmacogenetics will depend on how competing interests and options are resolved.     

Pharmacogenetics education in British medical schools

Pharmacogenetic tests allow medications to be tailored to individual patients to improve efficacy and reduce drug toxicity. In 2005, the International Society of Pharmacogenomics (ISP) made recommendations for undergraduate medical teaching in pharmacogenetics. We aimed to establish the quantity and scope of this in British medical schools. An electronic survey was sent to all British medical schools. Nineteen out of 34 (56%) medical schools responded. Sixteen of the 19 (84%) respondents provided pharmacogenetics teaching, usually 1–2 h in total. Only four (21%) medical schools offered the four or more hours of teaching recommended by the ISP. However, 10 of 16 (63%) schools felt the amount of pharmacogenetic teaching offered was sufficient. The quantity of undergraduate teaching of pharmacogenetics is low. However, a majority of UK medical schools teach it, covering a broad scope of elements. It is encouraging that future clinicians are being provided with the knowledge to deliver pharmacogenetics into clinical practice.     

Pharmacogenetic testing, informed consent and the problem of secondary information

Numerous benefits for patients have been predicted if prescribing decisions were routinely accompanied by pharmacogenetic testing. So far, little attention has been paid to the possibility that the routine application of this new technology could result in considerable harm to patients. This article emphasises that pharmacogenetic testing shares both the opportunities and the pitfalls with 'conventional' disease-genetic testing. It demonstrates that performing pharmacogenetic tests as well as interpreting the results are extraordinarily complex issues requiring a high level of expertise. It further argues that pharmacogenetic testing can have a huge impact on clinical decisions and may influence the therapeutic strategy as well as the clinical monitoring of a patient. This view challenges the predominant paradigm that pharmacogenetic testing will predict patients' responses to medicines, but that it will not provide any other significant disease-specific predictive information about the patient or family members. The article also questions published proposals to reduce the consent procedure for pharmacogenetic testing to a simple statement that the physician wishes to test a sample of the patient's DNA to see if a drug will be safe or whether it will work, and presents an alternative model that is better suited to protect patient's interests and to obtain meaningful informed consent. The paper concludes by outlining conditions for the application of pharmacogenetic testing in clinical practice in a way that can make full use of its potential benefits while minimising possible harm to patients and their families.     

Prevalence and distribution of genetic diseases in Quebec: impact of the past on the present

The prevalence and distribution of genetic diseases in the province of Quebec has been influenced by its population history. The current French Canadian population stems from 8,500 pioneers who left France for Nouvelle-France between 1608 and 1759. After the English conquest of Nouvelle-France in 1759, the French Canadian population remained mostly genetically isolated, for linguistic, cultural, and religious reasons. The migration of a small number of French individuals to Nouvelle-France created a founder effect. Subsequent migrations inland have created smaller regional founder effects. The limited size of the population favoured genetic drift, and the social context encouraged endogamy, i.e. unions between French Canadians with little admixture with English and other immigrants. Founder effects, genetic drift, and endogamy have all played a role in the current prevalence and distribution of genetic diseases now found in Quebec. The prevalence and distribution of genetic diseases in Quebec need to be taken into account in clinical practice. When clinicians are knowledgeable about the genetic diseases prevalent in the population they treat, they know to consider these diseases in differential diagnoses when appropriate and prioritize investigations accordingly. When developing a new diagnostic test for a genetic disease, the prevalence of the disease and the nature of the mutations found in the target population need to be taken into account. The performance of the test will depend on how well it accounts for the particularities of the disease in that population. In other words, how well does it detect the mutations found in that population? Interpretation of individual genetic test results will also depend on how well the test is expected to perform in the individual's population.     

Pharmacogenetics in Primary Care: The Promise of Personalized Medicine and the Reality of Racial Profiling

Many anticipate that expanding knowledge of genetic variations associated with disease risk and medication response will revolutionize clinical medicine, making possible genetically based Personalized Medicine where health care can be tailored to individuals, based on their genome scans. Pharmacogenetics has received especially strong interest, with many pharmaceutical developers avidly working to identify genetic variations associated with individual differences in drug response. While clinical applications of emerging genetic knowledge are becoming increasingly available, genetic tests for drug selection are not as yet widely accessible, and many primary care clinicians are unprepared to interpret genetic information. We conducted interviews with 58 primary care clinicians, exploring how they integrate emerging pharmacogenetic concepts into their practices. We found that in their current practices, pharmacogenetic innovations have not led to individually tailored treatment, but instead have encouraged use of essentialized racial/ethnic identity as a proxy for genetic heritage. Current manifestations of Personalized Medicine appear to be reinforcing entrenched notions of inherent biological differences between racial groups, and promoting the belief that racial profiling in health care is supported by cutting-edge scientific authority. Our findings raise concern for how pharmacogenetic innovations will actually affect diverse populations, and how unbiased treatment can be assured.     

Parental attitudes toward genetic testing for pediatric deafness

Recent molecular genetic advances have resulted in genetic testing becoming an option for deaf individuals and their families. However, there is little information about the interest in such testing. To investigate this issue, parents with normal hearing who have one or more deaf children were surveyed about their attitudes toward diagnostic, carrier, and prenatal genetic testing for deafness. This population was chosen because it represents the majority of individuals who are encountered in clinical practice, given that 90%-95% of deaf individuals are born to persons with normal hearing. Of 328 surveys distributed, 96 were completed and returned. Of the respondents, 96% recorded a positive attitude toward genetic testing for deafness, including prenatal testing, although none would use this information to terminate an affected pregnancy. All respondents had a poor understanding of genetics, with 98% both incorrectly estimating the recurrence risk of deafness and misunderstanding the concept of inheritance. Notably, these findings were similar in the group who had had genetic testing for their children and in the group who had not, suggesting either that the parents who received genetic testing did not receive genetic counseling or that the counseling was not effective. On the basis of these results, it was concluded that this population is interested in the use of genetic testing and that testing should not be done without first providing formal genetic counseling. Appropriate counseling can help parents to understand the risks, benefits, and limitations of genetic testing.